Neuropeptide Y (hereinafter referred to as NPY), a peptide consisting of 36 amino acids, was first isolated from porcine brain by Tatemoto et al in 1982 (NATURE, vol. 296, p. 659(1982)). NPY is widely distributed in central nervous system and peripheral nervous system, and plays various roles as one of the most abundant peptides in the nervous system. That is, NPY acts as an orexigenic substance in the central nervous system and markedly promotes fat accumulation via the mediation of secretion of various hormones or the action of the nervous system. It is known that continuous intracerebroventricular administration of NPY induces obesity and insulin resistance due to these actions (INTERNATIONAL JOURNAL OF OBESITY, vol. 19, p. 517 (1995); Endocrinology, vol. 133, p. 1753 (1993)). It is also known that NPY has central actions such as depression, anxiety, schizophrenia, pain, dementia, circadian rhythm control and the like (DRUGS, vol. 52, p. 371 (1996); THE JOURNAL OF NEUROSCIENCE, vol. 18, p. 3014 (1998)). Furthermore, in the periphery, NPY coexists with norepinephrine in sympathetic-nerve terminals and is related to the tonicity of the sympathetic nervous system. It is known that peripheral administration of NPY causes vasoconstriction and enhances the activities of other vasoconstrictive substances such as norepinephrine (BRITISH JOURNAL OF PHARMACOLOGY, vol. 95, p. 419 (1988)). It is also reported that NPY could participate in the development of cardiac hypertrophy as a result of the sympathetic stimulation (PROCEEDING NATIONAL ACADEMIC SCIENCE USA, vol. 97, p. 1595 (2000)).
On the other hand, it is reported that NPY is also involved in the secretory function of sexual hormones and growth hormone, sexual behavior and reproductive function, gastro-intestinal motility, bronchoconstriction, inflammation and alcohol preference (LIFE SCIENCE, vol. 55, p. 551 (1994); THE JOURNAL OF ALLERGY AND IMMUNOLOGY, vol. 101, p. S345 (1998); NATURE, vol. 396, p. 366 (1998)).
NPY has a variety of pharmacological effects resulting from NPY binding to the NPY receptors, to some of which other NPY related peptides including peptide YY and pancreatic polypeptide also bind. It is known that these pharmacological effects of NPY are mediated by the action of at least five receptors with or without synergistic interactions (TRENDS IN NEUROSCIENCE, vol. 20, p. 294 (1997)).
It is reported that the central effects mediated by NPY Y1 receptor include remarkable orexigenic effect (ENDOCRINOLOGY, vol. 137, p. 3177 (1996); ENDOCRINOLOGY, vol. 141, p. 1011 (2000)). Further, NPY Y1 receptor is reported to be involved in anxiety and pain (NATURE, vol. 259, p. 528 (1993); BRAIN RESEARCH, vol. 859, p. 361 (2000). In addition, the pressor effect mediated by the strong vasoconstrictor action in the periphery is also reported (FEBS LETTERS, vol. 362, p. 192 (1995); NATURE MEDICINE, vol. 4, p. 722 (1998)).
It is known that the effects mediated by NPY Y2 receptor include an inhibitory effect on the release of various neurotransmitters in the sympathetic nerve endings (BRITISH JOURNAL OF PHARMACOLOGY, vol. 102, p. 41 (1991); SYNAPSE, vol. 2, p. 299 (1988)). In periphery, NPY Y2 causes constriction of blood vessel or vas deferens directly or via the control of release of various neurotransmitters (THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 261, p. 863 (1992); BRITISH JOURNAL OF PHARMACOLOGY, vol. 100, p. 190 (1990)). Inhibition of lipolysis in adipose tissues is also known (ENDOCRINOLOGY, vol. 131, p. 1970 (1992)). Further, inhibition of ion secretion in the gastro-intestinal tract is reported (BRITISH JOURNAL OF PHARMACOLOGY, vol. 101, p. 247 (1990)). On the other hand, the effect on the central nervous system functions such as memory, anxiety and the like are also known. (BRAIN RESEARCH, vol. 503, p. 73 (1989); PEPTIDES, vol. 19, p. 359 (1998)).
It is reported that NPY Y3 receptor exists mainly in brainstem and heart and is related to the regulation of blood pressure and heart rate (THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 258, p. 633 (1991); PEPTIDES, vol. 11, p. 545 (1990)). It is also known that NPY Y3 is involved in the control of catecholamine secretion in adrenal gland (THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 244, p. 468 (1988); LIFE SCIENCE, vol. 50, p. PL7 (1992)).
NPY Y4 receptor has high affinity for pancreatic polypeptide in particular. As for the pharmacological effects of NPY Y4, inhibition of pancreatic exocrine secretion and gastro-intestinal motility is reported (GASTROENTEROLOGY, vol. 85, p. 1411 (1983)). Further, it is reported that NPY enhances the secretion of sexual hormones in the central nervous system (ENDOCRINOLOGY, vol. 140, p. 5171 (1999)).
As for the effects mediated by NPY Y5 receptor, fat accumulation effects including orexigenic effect are prominent (NATURE, vol. 382, p. 168 (1996); AMERICAN JOURNAL OF PHYSIOLOGY, vol. 277, p. R1428 (1999 )). It is also reported that the NPY Y5 receptor mediates some CNS effects, such as seizure and epilepsy, or pain and morphine withdrawal symptoms, and the control of circadian rhythm (NATURE MEDICINE, vol. 3, p. 761 (1997); PROCEEDING NATIONAL ACADEMIC SCIENCE USA, vol. 96, p. 13518 (1999); THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 284, p. 633 (1998); THE JOURNAL OF NEUROSCIENCE, vol. 21, p. 5367 (2001). In addition, diuresis effect and hypoglicemic effect in the periphery are reported (BRITISH JOURNAL OF PHARMACOLOGY, vol. 120, p. 1335 (1998); ENDOCRINOLOGY, vol. 139, p. 3018 (1998)). NPY is also reported to enhance cardiac hypertrophy as a result of the sympathetic accentuation (PROCEEDING NATIONAL ACADEMIC SCIENCE USA, vol. 97, p. 1595 (2000)).
The effects of NPY are expressed when NPY binds to the NPY receptors in the central or peripheral nervous system. Therefore, the action of NPY can be prevented by blocking its binding to NPY receptors. For this reason, it is expected that substances antagonize NPY binding to NPY receptors may be useful for the prophylaxis or treatment of various diseases related to NPY, for example cardiovascular disorders such as angina, acute or congestive heart failure, myocardial infarction, hypertension, nephropathy, electrolyte abnormality, vasospasm, atherosclerosis, etc., central nervous system disorders such as bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal, circadian rhythm disorders, schizophrenia, memory impairment, sleep disorders, cognitive impairment, etc., metabolic diseases such as obesity, diabetes, hormone abnormality, gout, fatty liver, etc., genital or reproductive disorders such as infertility, preterm labor, sexual dysfunction, etc., gastro-intestinal disorders, respiratory disorder, inflammatory diseases or glaucoma, and the like. (TRENDS IN PHARMACOLOGICAL SCIENCE, vol. 15, p. 153 (1994); LIFE SCIENCE, vol. 55, p. 551 (1994); DRUGS, vol. 52, p. 371 (1996); THE JOURNAL OF ALLERGY AND IMMUNOLOGY, vol. 101, p. S345 (1998); NATURE, vol. 396, p. 366 (1998); THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 284, p. 633 (1998); TRENDS IN PHARMACOLOGICAL SCIENCE, vol. 20, p. 104 (1999); PROCEEDING NATIONAL ACADEMIC SCIENCE USA, vol. 97, p. 1595 (2000); THE JOURNAL OF NEUROSCIENCE, vol. 21, p. 5367 (2001); PHARMACOLOGY & THERAPEUTICS, vol. 65, p. 397 (1995)).
It was recently found that, as a result of the study by the present inventors, a certain NPY receptor antagonist is useful for the prophylaxis or treatment of hypercholesterolemia, hyperlipidemia and arteriosclerosis (International application publication WO99/27965).
International application publication WO00/27845 and WO01/14376 disclose a variety of carboxamide derivatives, and mention that said derivatives have excellent NPY receptor antagonistic activities. International application publication WO02/48152 discloses a variety of spiro(isobenzofuran-1,4′-piperidine)-3-on derivatives, and mentions that said derivatives have an effect to regulate the NPY binding to NPY5 receptors. However, none of the above international publications describes the compounds of the present invention.